Reducing adhesion

ABSTRACT

A method of reducing adhesion at a site of trauma includes forming a film from an alginate solution, contacting the film with a cross-linking solution to form a cross-linked mechanically stable sheet, and placing at least a portion of the sheet at the site of trauma. An anti-adhesion barrier includes a sheet of ionically cross-linked alginate having a thickness in a range of 0.25 mm to 10 mm. The sheet has a tear strength sufficient for suturing and repositioning. A drug delivery device includes a cross-linked alginate container that can be filled with a drug.

CROSS-REFERENCE TO RELATED CASE

This application is a continuation of U.S. application Ser. No.09/791,490, filed Feb. 23, 2001, and claims the benefit of and priorityto U.S. Provisional Patent Application Serial No. 60/185,223, filed Feb.25, 2000. The entirety of both of is incorporated herein by reference.

TECHNICAL FIELD

The invention generally relates to polymer medical devices for insertioninto a body.

BACKGROUND INFORMATION

Surgery or injury often leads to the problem of tissue adhesion. Forexample, injury, incision or abrasion of the peritoneum, pleural orabdominal cavity causes release of a serosanguinous exudate. The exudatecoagulates, which leads to production of fibrinous bands betweenabutting surfaces. These bands can organize by fibroblast proliferationto become collagenous adhesions.

Adhesions can also form at sites of bone fractures. Bony spurs promotethe formation of fibrous adhesions between the fracture site andneighboring tissue. Surgery caused adhesions are generally undesirable.For example, adhesions can impair normal movement between bones andtendons, cause bowel obstructions and disrupt nerve transmissions.

Approaches to reduction of post-surgical adhesion include theapplication of drugs or surfactants, and use of collagen,collagen-fabric, collagen membranes or reconstituted collagen asphysical barriers. Other barriers are made from polyester, collagen,amino acids polymers and chitin.

In situ methods of barrier formation have utilized carboxyl-containingpolysaccharides. Barriers can consist of a polysaccharide solution,covalently cross-linked polysaccharide or ionically cross-linkedpolysaccharide.

Hyaluronic acid (“HA”) is a polysaccharide that has been used foranti-adhesion applications. To provide greater stability, HA can becross-linked in a patient with a number of ionically cross-linkingsolutions, such a ferric chloride solution. Alginate is anotherpolysaccharide that can be used for anti-adhesion purposes. The barrieris formed at a desired site by simultaneous spraying of polysaccharidesolution and cross-linking solution, injection of solutions or spreadinga foam or gel at the site.

SUMMARY OF THE INVENTION

The invention generally involves low cost, easy to place and repositionanti-adhesion barrier sheets. Prior methods and devices for reduction oftrauma site adhesion have several deficiencies. In situ formation ofbarriers creates the need for use of more equipment and expenditure ofmore time and effort by a medical worker. In situ formation also leadsto a barrier of variable properties. The exact degree of cross-linking,thickness of a material, and location of the material will vary frompatient to patient. Prior methods of use of cross-linked polysaccharidesprevent easy removal of barrier material from a patient. Though muchused, HA is very expensive and provides barriers of limited physicalstability and lifetime.

The invention also generally involves adhesion barriers that have lowcost and are easy to use. Adhesion barriers according to the inventiondo not require in situ formation, have a lifetime in a body of up to twoweeks or more, and permit a medical worker to both reposition and fixthe barrier at a desired location. The invention generally relates to arepositionable, long life, low cost barrier sheet that a medical workercan suture to tissue. The invention also generally relates to acontainer-based drug delivery device.

In one aspect, the invention features a device for insertion into a bodyto reduce adhesion. The device comprises a sheet comprising ionicallycross-linked alginate. The sheet has sufficient mechanical stability toallow suturing of the sheet to a body tissue. The sheet provides abarrier to reduce adhesion between the body tissue and a neighboringbody tissue.

In one embodiment, the sheet has a thickness in a range of 0.25 mm to 10mm. In a further embodiment, the sheet has a tear strength in a range of5 psi to 500 psi. In a further embodiment, the sheet can be fabricated,or cut by a medical worker, in a variety of shapes, including a polygon,an oval and a disk. In another embodiment, more than 25 wt % of thesheet is water.

In one embodiment, an outer portion of the sheet has a lower density ofcross-linking relative to an inner portion of the sheet. In a furtherembodiment, the device includes a suture for tying the sheet to atissue.

In another aspect, the invention features a drug delivery device forinsertion in a body. The device comprises a container that comprisesmechanically stable ionically cross-linked alginate. In one embodiment,the container is filled with one or more drugs and inserted in a body.

In one aspect, the invention features a method of forming a sheet foruse as an adhesion barrier. The method comprises forming a film from analginate solution, and contacting the film with a cross-linking solutionto form a cross-linked mechanically stable sheet. At least a portion ofthe sheet can be placed at a site of trauma to create the adhesionbarrier. In one embodiment, the method includes suturing the portion ofthe sheet to secure it to the site of trauma.

In one embodiment, the method further comprises selecting a quantity ofthe alginate solution to yield a sheet having a thickness in a range of0.25 mm to 10 mm. In another embodiment, contacting comprises waiting apreselected period of time to obtain a preselected density ofcross-linking. In one embodiment, the alginate film is stored prior tocontacting with the cross-linking solution.

In one embodiment, contacting is accomplished by pouring. In anotherembodiment, contacting is accomplished by spraying. In still anotherembodiment contacting is accomplished by extrusion of the film ofalginate solution into a bath of cross-linking solution.

In one embodiment, the film from an alginate solution is formed bydipping a substrate into a bath of the alginate solution. In anotherembodiment, contacting is accomplished by dipping the substrate in abath of the cross-linking solution.

In a further embodiment, the cross-linked mechanically stable sheet iscontacted with an ion stripping agent to reduce a density ofcross-linking in an outer portion of the sheet relative to an innerportion of the sheet.

In one embodiment of the invention, the alginate solution compriseswater and a water soluble alginate selected from the group consisting ofsodium alginate, potassium alginate, magnesium alginate or propyleneglycol alginate.

In one embodiment, the cross-linking solution comprises a divalent ortrivalent metal salt. The salt can be, for example, a salt of barium,calcium, copper, cobalt, aluminum, iron, boron, beryllium, lead orsilver. In another embodiment, the alginate solution comprises alginicacid having an active ester or aldehyde at a carboxylate site, and thecross-linking solution comprises a bifunctional cross-linker.

In another embodiment, the alginate solution comprises a filler. Thefillers can be radiopaque materials to allow visualization of thebarrier within the body, both during and after placement at a desiredtarget site. The fillers can be materials that increase the mechanicalstrength of the barrier, for example pieces of non-dissolvable polymermaterial, such as suture material, or other non-dissolvable materials.In another embodiment, the filler is a lifetime enhancer that comprisesa sulfate of calcium, barium, strontium, copper, zinc or iron.

In another embodiment, the alginate solution includes one or morepolymers selected from the group consisting of a biodegradable polymer,a polysaccharide, a polyester and a polymer with covalent cross-linking.The polymers are selected to modify the elastic modulus andhydrophobicity of the sheet.

In another embodiment, the alginate solution comprises an additive formedical treatment, for example, an antiseptic, an antibiotic, ananticoagulant, a contraceptive, a nucleic acid molecule, a protein, anda medicine. In another embodiment, the alginate solution comprises abiocompatible dye to assist observation of sheet location in a body. Inother embodiments of the invention, a filler or other additive isincluded in the cross-linking solution.

In another aspect, the invention provides a method of making a drugdelivery device for insertion in a body. The method comprises forming afilm from an alginate solution, and contacting the film with across-linking solution to cross-link an outer portion of the film. Aninterior portion of the film remains substantially non-cross-linked andis drained through an opening in the outer portion. In one embodiment,the outer portion is then filled with one or more drugs and inserted ina body. In another embodiment, the method further comprises insertingcross-linking solution into the drained outer portion to furthercross-link the outer portion.

The foregoing and other objects, aspects, features, and advantages ofthe invention will become more apparent from the following descriptionand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention.

FIGS. 1a-1 d are illustrations of a method of reducing adhesion at asite of trauma, according to an embodiment of the invention. FIG. 1ashows formation of a film. FIG. 1 b shows contacting the film with across-linking solution. FIG. 1c shows allowing contact to continue for aperiod of time. FIG. 1d shows a mechanically stable, cross-linked sheet.

FIG. 2 illustrates spraying a cross-linking solution on a film ofalginate solution.

FIG. 3 illustrates contacting a film of alginate solution with across-linking solution by extrusion.

FIG. 4 is a cross-sectional illustration of an embodiment of a film thatincludes filler.

FIG. 5 is an illustration of an embodiment of a sheet sutured to a bodytissue.

FIGS. 6a-6 c are illustrations of fabrication of a sheet with across-link density that varies across the sheet thickness. FIG. 6a showsa cross-linked sheet. FIG. 6b shows contact with an ion-stripping agent.FIG. 6c shows a sheet having greater cross-link density in an innerportion than in outer portions.

FIGS. 7a and 7 b are illustrations of making a drug delivery device.FIG. 7a shows a film that has received partial cross-linking to form acontainer filled with substantially non-cross-linked material. FIG. 7bshows draining the substantially non-cross-linked material through anopening in the container.

DESCRIPTION

This invention relates to polymer medical devices for insertion into abody and methods for making such devices. More particularly, theinvention relates to cross-linked alginate barriers for reduction ofpost-surgical body tissue adhesion. The medical devices according to theinvention are suitable for both human and animal use.

In one aspect, the invention provides a mechanically stable cross-linkedalginate-based sheet that is fabricated and stored prior to use as abarrier in a body. A medical worker places the sheet at a desiredlocation in the body to reduce post-trauma adhesion at the location. Inanother aspect, the invention provides a cross-linked alginate-basedcontainer for drug delivery inside of a patient.

A site of trauma is here understood as a site of tissue injury thatincludes, though is not limited to, sites of incision, drying, suturing,excision, abrasion, contusion, laceration, anastomosis, manipulation,prosthetic surgery, curettage, orthopedic surgery, neurosurgery,cardiovascular surgery, and plastic or reconstructive surgery. Sites oftrauma are also here understood to include neighboring undamaged tissue.

The invention has application in various surgical procedures, suchas: 1) gynecological (myomectomy via laparotomy or laparoscopy)—duringremoval of a fibroid, an incision is made in the uterus, and a barriercan be placed in between the uterus and the surrounding tissues toprevent adhesion; 2) abdominal—an adhesion barrier can be used toprevent peritoneal adhesions and therefore prevent intestinalobstruction; 3) cardiac—a barrier can be used to prevent post-operativeadhesion after cardiac procedures; 4) cranial—a barrier can protect theexposed cortex during craniotomy to prevent the skull and the cortexfrom adhering; and 5) musculoskeletal—a barrier can prevent adherence ofa tendon and the surrounding tissues.

Method for Sheet Formation and Adhesion Reduction

FIGS. 1a-1 d illustrate an embodiment of a method for reduction ofadhesion at a site of trauma. Alginate solution 1 is dispensed from aalginate solution dispenser 5 onto a substrate 7. As the solution 1 isdispensed, a film 20 of alginate solution 1 forms on the substrate 7. Insome embodiments, the substrate 7 comprises glass, a polymer, aluminumor steel.

Referring to FIG. 1b, after formation of the film 20, cross-linkingsolution 2 is dispensed from a cross-linking solution dispenser 6. Thecross-linking solution 2 contacts and surrounds the alginate solutionfilm 20.

Referring to FIG. 1c, after dispensing the cross-linking solution 2, thecross-linking solution 2 is allowed to remain in contact with thealginate solution film 20 for a desired amount of time. The amount oftime is varied to vary the degree of cross-linking and properties of thefilm 20. After sufficient cross-linking, a cross-linked mechanicallystable sheet 10 is removed from contact with the cross-linking solution2.

In one embodiment, the cross-linking solution 2 is poured onto thealginate solution film 20. In another embodiment, the film 20 forms whenthe alginate solution 1 is poured onto a film of the cross-linkingsolution 2.

FIG. 2 illustrates an alternative sheet 10 fabrication step that createscontact between an alginate film 20 a and cross-linking solution 2. Across-linking solution spray dispenser 200 sprays cross-linking solution2 onto an alginate film 20 a. The alginate film 20 a in one embodimentis suspended while in another embodiment the film 20 rests on asubstrate 7.

FIG. 3 illustrates another alternative sheet 10 fabrication step thatcreates contact between an alginate film 20 and cross-linking solution2. Films 20 b comprising alginate solution are extruded from anextrusion dispenser 300. The film 20 b is immersed in a cross-linkingsolution 2 held in a vessel 7 a.

In another embodiment, a substrate is dipped into alginate solution 20to coat the substrate with an alginate film 20. The alginate film 20 isthen contacted with cross-linking solution 2. This embodiment isparticularly useful for fabrication of thin sheets 20.

In one embodiment, the alginate solution 1 comprises water and a watersoluble alginate. In a preferred embodiment, the water soluble alginateis selected from the group consisting of sodium alginate, potassiumalginate, magnesium alginate or propylene glycol alginate. In oneembodiment, less than 40 wt % of the alginate solution 1 comprisessodium alginate.

In some embodiments, the cross-linking solution 2 comprises a divalentor trivalent metal salt. The salt can be selected, for example, fromsalts of the following metals: barium, calcium, copper, cobalt,aluminum, iron, boron, beryllium, lead and silver. In a preferredembodiment, less than 40 wt % of the cross-linking solution 2 comprisescalcium chloride. Greater cross-linking solution 2 concentrations willcause more rapid cross-linking of the alginate film 20 while lowerconcentrations will cause slower cross-linking.

The quantity of cross-linking ions required to fully cross-link thealginate film 20 is a function of the quantity of functional groups inthe film 20. Calcium ions, for example, react divalently with theguluronic acid part of alginate and monovalently with the mannuronicpart or alginate. So, the amount of calcium required depends on the acidratio.

In one embodiment, the contact time is varied to vary the degree ordensity of cross-linking in the sheet 10. This embodiment can beemployed to control the sheet 10 flexibility and lifetime. Typicalcontact times are in the range of seconds up to one hour.

In another embodiment, the alginate solution 1 comprises a surfactant. Asurfactant contributes to the ability of the alginate solution 1 tospread on the substrate 7, decreases surface tension of the sheet 10,and makes the sheet 10 more lubricious. Some surfactants can also act asa bactericide. For example, benzalkonium chloride is an effectivewetting agent and antimicrobial agent. The alginate solution 1 caninclude nonionic or ionic surfactants, though preferably surfactantsthat do not interfere with the cross-linking reaction should beselected.

In another embodiment, the alginate solution 1 comprises alginic acidhaving an active ester or aldehyde at a carboxylate site, and thecross-linking solution 2 comprises a bifunctional cross-liner. Thebifunctional cross-linker can comprise, for example, carbodiimide ordihydrazide.

After fabrication, a sheet 10 can be stored dry or wet, for example insterile water, saline solution or water containing hygroscopic agents,such as glycerol, sorbitol, sucrose, and the like (it should beunderstood that a sheet 10 can be cut to any desired shape at any stageof use or before storage). In another embodiment, the sheet 10 is driedprior to storage and rehydrated prior to use. The sheet 10 can besterilized as desired.

In some embodiments, the alginate solution film 20 is stored prior tocontacting with the cross-linking solution 2. The film 20 can be driedprior to storage, for example by air-drying or freeze-drying.

The sheet 10 typically has a high water holding capacity. In someembodiments, the sheet holds up to approximately on third its weight inwater. Other embodiments can hold over 99 % of their weight in water.For example, a sheet 10 experimentally prepared from a 4 wt % alginatesolution held approximately 90 wt % water.

Referring to FIGS. 6a-6 c, an embodiment is illustrated of a method offabricating a sheet 10 with a cross-link density that varies across thesheet thickness 10. After formation of a sheet 10 (FIG. 6a) as discussedabove, the sheet 10 is contacted with an ion-stripping agent 60 (FIG.6b). The agent 60 reduces the cross-link density in outer portions 12 ofthe sheet 10 by stripping ions from the outer portions 12. This leavesan inner portion 11 of the sheet with a greater cross-link density thanthe outer portions 12 (FIG. 6c).

The ion-stripping agent 60 can comprise an ion-stripping solution held,for example, in a vessel 7 b for immersion of the sheet 10. Theion-stripping solution can comprise, for example, EDTA or phosphateions. In another embodiment, a cross-linked alginate sheet 10 isextruded and disposed in the ion-stripping solution. Agents 60 and theirapplication are described in more detail below.

In another aspect of the invention, a method for in situ barrierformation is provided. In one aspect, the method comprises sequentiallycoating a trauma site with an alginate solution and a cross-linkingsolution. In one embodiment, a film of alginate solution is disposed atthe site of trauma. Subsequently, a cross-linking solution is contactedwith the film to form a cross-linked alginate barrier layer. In anotherembodiment, the crossing-linking solution is first coated on the desiredtissue location followed by contacting with the alginate solution.

Cross-Linked Polymers

Some embodiments of the sheet 10 comprise cross-linkable polymers inaddition to alginate. The anti-adhesion sheets 10 of one embodiment ofthe invention are fabricated from cross-linkable polymers which may beanionic or cationic in nature and include, but are not limited to,carboxylic, sulfate, hydroxy and amine-functionalized polymers, normallyreferred to as hydrogels after being cross-linked. The term “hydrogel”as defined herein is a cross-linked, water-insoluble, water-containing(e.g., hydrophilic) polymeric material.

Cross-linkable polymers used in some embodiments include one or amixture of polysaccharides (e.g., alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan,carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, carboxymethylstarch, carboxymethyl dextran, chondroitin sulfate, cationic guar,cationic starch, as well as salts and esters thereof). Polymers listedabove which are not ionically cross-linkable can be used in blends withpolymers which are ionically cross-linkable.

A preferred polymer is one based on alginic acid. These include sodiumalginate, potassium alginate, magnesium alginate and propylene glycolalginate.

Ionic Cross-linking

The cross-linkable polymers according to one aspect of the presentinvention use ionic cross-linking. In some embodiments, they further usenon-ionic (e.g., covalent) cross-linking. Ions used to ionicallycross-link the polymers are polyions and may be anions or cationsdepending on whether the polymer is cationically or anionicallycross-linkable.

Appropriate cross-linking cations include, but are not limited to,alkaline earth metals, such as calcium, magnesium, barium, strontium,and beryllium ions; transition metals, such as iron, manganese, copper,cobalt, zinc, and silver ions; other metallic elements, such as boron,aluminum, lead, and bismuth ions; and polyamonium ions, such as⁺H₃N(—CH₂)_(n)—NH₃ ⁺ or ⁺H₃N—(CH₂)_(n)—CH((CH₂)_(m)—NH₃ ⁺)((CH₂)_(p)—NH₃⁺) where n is an integer ranging from 1 to 8, and m and p are integersranging from 0 to 8 ions.

Anions are derived from polybasic organic or inorganic acids.Appropriate cross-linking anions include, but not limited to, phosphate,sulfate, citrate, borate, succinate, maleate, adipate and oxalate ions.

Preferred cross-linking cations are calcium, iron, and barium ions. Themost preferred cross-linking cations are calcium and barium ions. Themost preferred cross-linking anion is phosphate. Cross-linking may becarried out by contacting the polymers with an aqueous solutioncontaining dissolved ions.

Sheet Mechanical Properties

In one aspect, the invention provides a suturable sheet 10. Todemonstrate the mechanical stability of sheets 10 of the invention, foursample sheet 10 portions were prepared from alginate solution 1 ofvarying alginate concentration.

Table I gives mechanical pull strength test data for sheet 10 samplesprepared from alginate solutions 1 of four different sodium alginateconcentrations. Sheets 10 of approximately 0.5 mm thickness werepermitted to fully cross-link prior to removal from a cross-linkingsolution 2 of 30 wt % calcium chloride. For mechanical testing, portionsof each sheet 10 0.4 inch wide and approximately 0.5 inch long receivedconventional Instron pull testing to failure.

TABLE I load at displacement tear force alginate tearing at tearing(lb/square conc. (wt %) (lb) (inch) inch) 8 2.09 0.91 290 7 1.30 0.55212 6 2.10 0.51 111 2 0.83 0.31 22

A sheet 10 preferably has a thickness in a range of 0.25 mm to 10 mm andmore preferably in a range of 0.5 mm to 5 mm to provide both sufficientstrength for suturing and sufficient flexibility to conform to thesubject tissue.

Referring to FIG. 5, suturing is illustrated. A portion of a sheet 50has been fabricated in a square shape and attached with sutures 55 totissue 57 at a site to be protected from formation of adhesion. Theportion of a sheet 50 can be fabricated or cut at time of use to anyconvenient shape, for example, round, oval or polygonal.

Fillers

Referring to FIG. 4, in some embodiments the alginate solution 20includes filler 40. The filler 40 can comprise particles, as illustratedin FIG. 4, or other material to modify various properties of the sheet10. Fillers 40 that can serve in various embodiments are now described.

Radiopaque materials can be included in the alginate solution 20 tomodulate the degradation rate, mechanical properties and increase thevisibility under x-ray imaging of the sheet 10. Suitable radiopaquefillers include, but are not limited to, bismuth sub-carbonate, bariumsulfate, bismuth oxychloride, tungsten, bismuth trioxide, tantalum, andthe like. Such fillers 40 can facilitate visualization of the sheet 10and a wound bed during healing through use of minimally invasivetechnology, such as fluoroscopic or x-ray imaging.

Other additives may be incorporated into the sheet 10 including, but notlimited to, additives for medical treatment, such as antiseptics,antibiotics, contraceptives, nucleic acids [e.g., DNA (including genes,cDNAs and vectors), RNA, antisense molecules, ribozymes, PNA molecules],proteins (e.g., ligands, receptors, growth factors, cytokines,vascularizing agents, anti-vascularizing agents, antibodies, and thelike), or medicines.

The hemostatic properties of the sheet 10 may be enhanced by theaddition of anticoagulants, antithrombotic or other hemostaticcompounds. For example, anticoagulants may be, but are not limited to,heparin, hirudins, thrombin, vasopressin and their derivatives.

The sheet 10 can comprise drugs. These drugs can include, for example,antibiotics such as β-lactams such as penicillins or cephalosporins,sulfonamides, quinolones floxacin and its derivatives, tetracyclines,macrolides such as erythromycin and its derivatives. These activesubstances may improve thrombogenicity and may significantly reducehealing time and reduce risk of infections.

In a further embodiment of the invention, filler 40 can be included tomodify mechanical properties, such as elastic modulus, or hydrophobicityof the sheet 10. Appropriate fillers include biodegradable polymers,polysaccharides, polyesters and polymers possessing covalentcross-linking.

In one embodiment of the invention, biodegradable suture materials orother non-dissolvable filler materials, may be incorporated into thesheet 10 to provide additional mechanical strength. Biodegradablepolymers include polyesters (such as polylactic acid (PLA), polyglycolicacid (PGA), polycaprolactone, copolymers of lactic acid, glycolic acid,and ε-caprolactone), other polysaccharides (such as cellulose and itswater soluble derivatives or HA) or polymers with covalent cross-links(such as polymer derivatized with polyaziridine compounds). In someembodiments, biodegradable polymers are included in the alginatesolution 1. In other embodiments, biodegradable polymers are applied toa surface of the sheet 10.

In another embodiment, the alginate solution 1 can comprise abiocompatible dye. Suitable dyes include FD&C blue No. 1, FD&C blue No.2, FD&C green No. 3, FD&C green No. 5, FD&C yellow No. 5, FD&C yellowNo. 6, FD&C yellow No. 10, β carotene, ginseng violet and food blue.Inclusion of such dyes in a sheet 10 can improve visibility of the sheetfor positioning and repositioning.

In another embodiment, the filler 40 comprises a lifetime enhancer. Alifetime enhancer gradually releases cross-linking ions to replace thosebeing lost from cross-linking sites in the sheet 10. While residing in abody, body fluids act to strip cross-linking ions from the sheet 10 (theaction of ion stripping agents is discussed in more detail in a latersection). Suitable lifetime enhancer materials include, for example,calcium sulfate, barium sulfate, strontium sulfate, copper sulfate, zincsulfate and iron sulfate.

For example, the alginate solution 1 can include 10 wt % to 20 wt %calcium sulfate that will act as a cross-linking ion reservoir for thecompleted sheet 10. As calcium ion cross-linkers are lost from the sheet10, additional calcium ions are derived from the reservoir until thereservoir is depleted.

Drug Delivery Device

In another aspect, the invention provides a drug delivery device. In oneembodiment, the device comprises an cross-linked alginate containerfilled with a drug. The container is placed within a body to graduallyrelease the drug.

Referring to FIGS. 7a and b, an embodiment of a method for making a drugdelivery device is illustrated. A film 70 is formed from an alginatesolution 1, for example as described above. The outer surface 73 of thefilm 70 is contacted with cross-linking solution 2 to form a container75. The container 75 comprises a cross-linked outer portion of the film70 adjacent to the outer surface 73. An interior fluid portion 72 of thefilm 70, adjacent to an interior wall 77 of the container 75, remainssubstantially non-cross-linked, for example by limiting thecross-linking time or the available quantity of cross-linking ions inthe cross-linking solution 2. The container 75 defines an interior space78 that initially is filled with the substantially non-cross-linkedinterior fluid portion 72 of the film 70. The substantiallynon-cross-linked interior fluid portion 72 is drained from the container75 through an opening 79 in the container 75.

In one embodiment, cross-linking solution 2 is inserted into the emptiedinterior space of the container 75 to cross-link the interior wall 77 ofthe container 75. In one embodiment, the container 75 is filled with adrug, sealed and inserted into a body for gradual release of the drugwithin the body.

Non-Ionic Cross-linking

In one embodiment of the invention, the cross-linkable polymers formingthe sheet 10 of this invention include non-ionic cross-linkingmechanisms to produce a sheet 10 having a higher cross-link density andimproved mechanical properties, i.e., improved stiffness, modulus, yieldstress and strength. This may be accomplished by additionally subjectingthe ionically cross-linkable polymer to non-ionic cross-linkingmechanisms such as high energy radiation (gamma rays) or treatment witha chemical cross-linking agent which reacts with groups present in thepolymer such that covalent bonds are formed connecting differentportions of the polymer or between polymer strands to form a web.Another non-ionic cross-linking mechanism useful with respect to someclasses of hydrogel polymers is physical cross-linking. This isaccomplished by crystal formation or similar association of polymerblocks such that the polymer molecules are physically tied together andprevented from complete dissolution. Non-ionic cross-linking may becarried out prior to, subsequent to, or concurrently with, ioniccross-linking.

A preferred method for non-ionic cross-linking is contact of anionically cross-linkable polymer with a chemical cross-linking agentbecause the degree of cross-linking can be controlled mainly as afunction of the concentration of the cross-linking agent. Suitablecross-linking agents are polyfunctional compounds preferably having atleast two functional groups reactive with one or more functional groupspresent in the polymer. The cross-linking agent can contain one or moreof carboxyl, hydroxy, epoxy, halogen, amino functional groups orhydrogen unsaturated groups, which are capable of undergoing facilenucleophilic or condensation reactions at temperatures up to about 100°C. with groups present along the polymer backbone or in the polymerstructure. Suitable cross-linking reagents include polycarboxylic acidsor anhydrides; polyamines; epihalohydrins; diepoxides; dialdehydes;diols; carboxylic acid halides, ketenes and like compounds. A preferredcross-linking agent is glutaraldehyde.

In one embodiment, cross-linkable polymers are provided which possesspendant organic acid functional groups which are covalentlycross-linkable with polyfunctional cross-linking agents. In thisembodiment of the invention, the covalent bonds between thecross-linking agents and the hydrophilic polymers are susceptible tohydrolysis in the body, releasing water-soluble components.

For purposes of the present invention, the term “organic acid functionalgroup” includes any functional group which contains an acidic, ionizablehydrogen. Examples of such functional groups include free carboxylic,free sulfuric, and free phosphoric acid groups, their metal salts andcombinations thereof. Such metal salts include, for example, (1) alkalimetal salts, such as lithium, sodium and potassium salts, (2) alkalineearth metal salts, such as calcium or magnesium salts, and (3)quaternary amine salts of such acid groups, particularly quaternaryammonium salts.

One embodiment utilizes cross-linking agents that can form relativelyweak covalent cross-linking bonds, so that these bonds can be “unzipped”or “de-cross-linked” within the body after a desired length of time. Forexample, polymers comprising covalent bonds that are easily hydrolysableat temperature and pH conditions inside the body can serve this purpose.Such polyfunctional covalent cross-linking agents include polyfunctionalaziridines, polyfunctional carbodiimides, polyisocyanate, glutaraldehydeor other polyfunctional cross-linkers wherein the functional groups arecapable of reacting with the organic acid groups, or any activated formsthereof.

In one embodiment, an alginate film 20 is dipped consecutively into twobaths, each bath containing one type of cross-linking agent. Forexample, the entirety of the film 20 may be dipped into a first bathcontaining a solution of cross-linking cations to ionically cross-link aportion of the available cross-linking sites of the alginate; then, theat least partially ionically cross-linked film 20 is dipped into asecond bath containing a solution of covalent cross-linking agent tocovalently cross-link a portion, or all of, the remaining availablecross-linking sites of the hydrophilic material. The extent of each typeof cross-linking may be varied by varying the length of time of exposureof the sheet 10 to each type of cross-linking agent or, alternatively,by masking portions of the device.

Heterogeneous Polymers as Strengthening Filler

In one embodiment of the invention, the sheet 10 includes short segmentsof non-dissolvable, non-disintegratable polymer(s), or biodegradablesuture material. The segments may be spaced at regular or irregularintervals. Such non-dissolvable polymer(s) or biodegradable suturematerial(s) provide added strength to a sheet 10 undergoing dissolutionand/or disintegration.

Suitable non-dissolvable polymers include, but are not limited to,silicones, polyethylene oxides, polyvinyl alcohol, and the like.Suitable biodegradable suture materials are polymers of glycolic acid,ε-caprolactone, lactic acid, or copolymers thereof, and the like.Further embodiments utilize short or thin portions of non-dissolvablepolymer, such as strings or meshes.

Modification of Cross-link Density

In one embodiment, displacement of cross-linking ions from the sheet 10can be accomplished by flowing a solution containing a stripping agentaround the sheet 10. The stripping agent serves to displace, sequester,or bind, the cross-linking ions present in the ionically cross-linkedpolymer, thereby removing the ionic cross-links. Some stripping agentsare polyions capable of forming stable ionic bonds with the cations oranions disclosed above.

The choice of any particular stripping agent will depend on whether theion to be displaced is an anion or a cation. If the cross-linking agentis a cation, then the stripping agent will be a polyanion, while if thecross-linking agent is an anion, the stripping agent will be apolycation. Suitable stripping agents include, but are not limited to,organic acids and their salts or esters, phosphoric acid and salts oresters thereof, sulfate salts and alkali metal or ammonium salts.

Examples of stripping agents include, but are not limited to, ethylenediamine tetraacetic acid, ethylene diamine tetraacetate, citric acid andits salts, organic phosphates, such as cellulose phosphate, inorganicphosphates, such as, pentasodium tripolyphosphate, mono and dibasicpotassium phosphate, sodium pyrophosphate, phosphoric acid, trisodiumcarboxymethyloxysuccinate, nitrilotriacetic acid, maleic acid, oxalate,polyacrylic acid, as well as sodium, potassium, lithium, calcium andmagnesium ions.

In one embodiment, the stripping step is accomplished by dipping orspraying the sheet 10 with an aqueous electrolyte solution for anappropriate time to selectively strip the cross-linking ions from thedevice. Some electrolytes for stripping are chlorides of monovalentcations such as sodium, potassium or lithium chloride, as well as otherstripping salts described above. The concentration of the electrolytesalt in the solution may range from approximately 1 wt % up to thesolubility limit. The solution may also contain plasticizingingredients, such as glycerol or sorbitol, to facilitate inter- andintra-polymer chain motion for shaping of the sheet 10.

Variations, modifications, and other implementations of what isdescribed herein will occur to those of ordinary skill in the artwithout departing from the spirit and the scope of the invention asclaimed. Accordingly, the invention is to be defined not by thepreceding illustrative description but instead by the spirit and scopeof the following claims.

What is claimed is:
 1. A method for forming a device for insertion intoa body, comprising: providing a substrate; forming a film comprising analginate solution on the substrate; and contacting the film with across-linking solution.
 2. The method of claim 1, wherein forming thefilm comprises disposing the film on a portion of the substrate.
 3. Themethod of claim 1, wherein the substrate has a first side and an opposedsecond side, and forming the film comprises disposing the film only onthe first side of the substrate.
 4. The method of claim 1, furthercomprising removing the film from the substrate after contacting thefilm, wherein the film is conformable to a body tissue.
 5. The method ofclaim 4, further comprising altering a shape of the film after removingthe film from the substrate.
 6. The method of claim 1, wherein formingthe film comprises dipping the substrate in a bath of the alginatesolution.
 7. The method of claim 1, wherein contacting the film with thecross-linking solution comprises spraying the cross-linking solutiononto the film on the substrate.
 8. The method of claim 1, whereincontacting the film with the cross-linking solution comprises dippingthe substrate in a bath of the cross-linking solution.
 9. The method ofclaim 1, wherein the alginate solution comprises one or more drugs. 10.The method of claim 1, wherein the substrate comprises a materialselected from the group consisting of glass, polymer, aluminum andsteel.
 11. The method of claim 1, wherein the alginate solutioncomprises a filler.
 12. The method of claim 11, wherein the filtercomprises a radiopaque material.
 13. A method for forming a medicaldevice, comprising: forming a film from a solution comprising across-linkable polymer; and contacting the film with a cross-linkingsolution to form a cross-linked mechanically stable barrier forplacement of the barrier at a site of trauma to provide an adhesionbarrier.
 14. The method of claim 13, wherein the cross-linkable polymercomprises a polysaccharide.
 15. The method of claim 14, wherein thesolution further comprises one or more drugs.
 16. The method of claim14, wherein the solution further comprises a filler.
 17. A method forforming a device for use as an adhesion barrier, comprising: forming afilm from a solution comprising a cross-linkable polymer; and exposingthe film to at least one non-ionic cross-linking mechanism.
 18. Themethod of claim 17, wherein the at least one non-ionic cross-linkingmechanism comprises at least one of covalent bonds and physicalcross-linking.
 19. The method of claim 17, wherein the cross-linkablepolymer comprises an alginate.
 20. The method of claim 17, wherein thesolution comprises more than one cross-linkable polymer.
 21. A methodfor reducing adhesion at a site of trauma, comprising: disposing a filmof a solution comprising a cross-linkable polymer at the site of trauma;and contacting the film disposed at the site of trauma with across-linking solution to form a cross-linked barrier layer.
 22. Themethod of claim 21, whereby the barrier layer has a thickness in a rangeof 0.25 mm to 10 mm.
 23. The method of claim 21, whereby the barrierlayer has a tear strength in a range of 5 psi to 500 psi.
 24. A methodfor reduction of adhesion at a site of trauma, comprising: disposing afilm of cross-linking solution at the site of trauma; and contacting thefilm disposed at the site of trauma with a solution comprising across-linkable polymer to form a cross-linked barrier layer.